Report
Drug-Drug Interaction between Azathioprine and Allopurinol in Patients with Chronic Kidney Disease: A Case Series Study
2021 Volume 4 Issue 5 Pages 170-174
Details
2021 Volume 4 Issue 5 Pages 170-174
The impact of renal impairment on the drug-drug interaction between azathioprine and allopurinol that causes myelosuppression and hepatotoxicity remains unclear. This case series study investigated adverse effects caused by azathioprine owing to drug-drug interaction considering renal impairment. Patients who started the combination therapy of azathioprine and allopurinol at Mie University Hospital between January 2013 and February 2021 were enrolled. The outcome of adverse events associated with azathioprine was assessed according to Common Terminology Criteria for Adverse Events version 5.0. The Drug Interaction Probability Scale was used to determine the probability of drug-drug interaction. Of the three patients, two were identified as exhibiting drug-drug interaction with the Drug Interaction Probability Scale > 5 points. They experienced grade 3 myelosuppression or hepatotoxicity with fatigue, after initiation of azathioprine (1.28 and 0.44 mg/kg once daily) and allopurinol (50 mg once daily). They received appropriate dose-adjusted allopurinol according to renal function. Additionally, both patients had the estimated glomerular filtration rate < 60 mL/min/1.73 m2. Thus, renal impairment might reduce the excretion of oxypurinol, an active metabolite of allopurinol, which certainly enhances the side effects of azathioprine.
Azathioprine is metabolized to 6-mercaptopurine, which is further transformed into pharmacologically active metabolites, such as 6-thioguanine nucleotides (one of the end metabolites).1) Clinically, azathioprine exhibits an immunomodulatory effect against autoimmune diseases, at a daily dose of 2.0 to 2.5 mg/kg.2–4) A high intracellular concentration of 6-thioguanine nucleotides is responsible for the development of myelosuppression.5,6) Additionally, 6-methylmercaptopurine ribonucleotide (another end metabolite of azathioprine), which blocks de novo purine synthesis, can cause hepatotoxicity.6)
Detoxification of 6-mercaptopurine involves via xanthine oxidase (XO).1) Thus, XO inhibitors, allopurinol and oxypurinol (an active metabolite of allopurinol), potentially inhibit the inactivation of 6-mercaptopurine, thereby increasing 6-thioguanine nucleotides concentrations and the risk of myelosuppression or hepatotoxicity. When azathioprine is co-administered with allopurinol, a 25% to 33% dose reduction of azathioprine is recommended to reduce the risk of toxicity.7) Oxypurinol is mainly eliminated via the kidney, and allopurinol is recommended to reduce the dose according to the nomogram based on renal function.8) Additionally, pharmacokinetic simulation demonstrated that the oxypurinol concentration at steady-state surpassed the concentrations to produce a 50% hypouricemic effect in patients with allopurinol 100 mg once daily and creatinine clearance of 20 mL/min.9,10) Thus, even low-dose allopurinol can sufficiently block XO activity in patients with reduced renal function.
In this study, we evaluated the clinical impact of renal function on drug-drug interaction between azathioprine and allopurinol.
This case series study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Mie University Hospital (approval number: H2021-099). The eligibility criteria included inpatients or outpatients who had initiated combination therapy of azathioprine and allopurinol at Mie University Hospital between January 2013 and February 2021. The exclusion criteria were as follows: (1) age < 15 years, (2) initiation of combination therapy with azathioprine and allopurinol at other hospitals, or (3) lack of data regarding clinical laboratory data or azathioprine dose.
Data CollectionWe collected the clinical data (e.g., age, body weight, and medications) from electrical medical records. We checked concurrent medications known to affect oxypurinol concentration such as uricosuric agent and furosemide.8) Renal function was calculated using the prediction formula of estimated glomerular filtration rate (eGFR) as follows: eGFR = 194 × serum creatinine−1.094 × age−0.287 × 0.739 (if female).11) eGFR < 60 mL/min/ 1.73 m2 for at least three months was diagnosed as chronic kidney disease.12)
OutcomeThe occurrence of adverse events associated with azathioprine (e.g., myelosuppression) was considered the outcome according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.13) We determined the probability of drug-drug interaction between azathioprine and allopurinol using the Drug Interaction Probability Scale (DIPS).14) A DIPS of > 5 points indicates that a causal drug-drug interaction is probable or highly probable. The follow-up duration was defined as the period from the initiation of combination therapy to the day of improvement in adverse events. If there were no adverse events, the follow-up duration was defined as the period from the initiation of combination therapy to the day of treatment discontinuation or February 2021.
We identified five patients who received the combination therapy of azathioprine and allopurinol during the study. Two patients were excluded because they started the combination therapy at another hospital. Finally, we analyzed three outpatients in this study (Table 1). Two patients (patients 1 and 2) received a combination therapy of azathioprine (1.28 and 0.44 mg/kg once daily, respectively) and low-dose allopurinol (50 mg once daily). In contrast, the third patient (patient 3) received azathioprine (0.88 mg/kg once daily) in combination with high-dose allopurinol (100 mg twice daily). All patients fulfilled the diagnostic criteria for chronic kidney disease and received dose-adjusted allopurinol based on renal function as the nomogram recommended.8) There were no concurrent medications influencing blood oxypurinol concentration. Two out of the three patients developed adverse events associated with azathioprine, and both patients had a DIPS score of > 5 points (Table 2).
| Patient | Sex | Age, years | BW, kg | BMI, kg/m2 | Diagnosis | AZA, mg/d (mg/kg/d) | ALL, mg/d | sCr, mg/dL | eGFR, mL/min/1.73m2 | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 79 | 39.2 | 16.1 | AAV | 50 (1.28) | 50 | 1.82 | 21.2 | Yes |
| 2 | M | 58 | 57.0 | 18.6 | UC | 25 (0.44) | 50 | 1.58 | 36.7 | Yes |
| 3 | M | 42 | 56.7 | 21.1 | CD | 50 (0.88) | 200a | 1.15 | 57.0 | No |
Abbreviations: BW, body weight; BMI, body mass index; AZA, azathioprine; ALL, allopurinol; sCr, serum creatinine; eGFR, estimated glomerular filtration rate; F, female; M, male; AAV, antineutrophil cytoplasmic antibody-associated vasculitis; UC, ulcerative colitis; CD, Crohn's disease.
We calculated the eGFR as follows: eGFR = 194 × serum creatinine−1.094 × age−0.287 × 0.739 (if female).11)
a: 100 mg twice daily
| Question | Patient 1 | Patient 2 | |
|---|---|---|---|
| 1 | Are there previous credible reports of this interaction in humans? | Y (+1) | Y (+1) |
| 2 | Is the observed interaction consistent with the known interactive properties of precipitant drug? | Y (+1) | Y (+1) |
| 3 | Is the observed interaction consistent with the known interactive properties of object drug? | Y (+1) | Y (+1) |
| 4 | Is the event consistent with the known or reasonable time course of the interaction (onset and/or offset)? | Y (+1) | Y (+1) |
| 5 | Did the interaction remit upon dechallenge of the precipitant drug with no change in the object drug? | NA (0) | NA (0) |
| 6 | Did the interaction reappear when the precipitant drug was readministered in the presence of continued use of object drug? | NA (0) | NA (0) |
| 7 | Are there reasonable alternative causes for the event? | N (+1) | N (+1) |
| 8 | Was the object drug detected in the blood or other fluids in concentrations consistent with the proposed interaction? | NA (0) | NA (0) |
| 9 | Was the drug interaction confirmed by any objective evidence consistent with the effects on the object drug? | Y (+1) | Y (+1) |
| 10 | Was the Interaction greater when the precipitant drug dose was increased or less when the precipitant drug dose was decreased? | NA (0) | NA (0) |
| Total scores (Causality of drug-drug interaction) | 6 (Probable) | 6 (Probable) | |
Abbreviations: Y: Yes, N: No, NA: not applicable.
The aforementioned scoring procedure was proposed by Horn et al.14) The object drug is azathioprine, and the precipitant drug is allopurinol. The answers and scores for each question were described. Drug interaction probability score categories are classified into four groups: doubtful (0–1), possible (2–4), probable (5–8), and highly probable (9–11).
Patient 1 received prednisolone therapy to control the further deterioration of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which the patient was diagnosed 252 days before the start of combination therapy. Patient 1 started azathioprine and allopurinol on day 0 because patient 1 had uncontrolled ANCA-associated vasculitis and high serum uric acid level (7.4 mg/dL). Patient 1 continued taking prednisolone 5 mg once daily during the follow-up period. Patient 2 started azathioprine to control the exacerbation of ulcerative colitis from day 0. Simultaneously, patient 2 continued the treatment of prednisolone (27.5 mg once daily) and 5-aminosalicylic acid (1,200 mg thrice daily). After patient 2 started on combination therapy of azathioprine and allopurinol, prednisolone was tapered by reducing the dose by 2.5 mg daily per week, followed by being discontinued.
Adverse EventsThe detail of adverse events was summarized in Table 3. Patient 1 developed grade 3 leucopenia, grade 3 neutropenia, and grade 3 anemia at the nadir, whereas patient 2 developed grade 3 elevation of γ-glutamyl transpeptidase and grade 2 elevation of alkaline phosphatase with fatigue at the nadir. Both patients experienced nadir adverse events associated with azathioprine after more than one month. The time to recovery from the development of adverse events at the nadir varied by the type of adverse event (leucopenia, 14 days; neutropenia, 7 days; anemia, 40 days; γ-glutamyl transpeptidase and alkaline phosphatase elevation; 63 days).
| Patient | Clinical outcome at the nadir | Time to outcomea, d | AZA | ALL | Recovery | Time to recoveryb, d |
|---|---|---|---|---|---|---|
| 1 | Grade 3 leucopenia | 37 | Discontinuedc | Discontinuedc | Yes | 14 |
| 1 | Grade 3 neutropenia | 44 | Discontinuedc | Discontinuedc | Yes | 7 |
| 1 | Grade 3 anemia | 44 | Discontinuedc | Discontinuedc | Yes | 40 |
| 2 | Grade 3 γ-GT elevation | 42 | Discontinuedd | Continued | Yes | 63 |
| 2 | Grade 2 ALP elevation | 42 | Discontinuedd | Continued | Yes | 63 |
Abbreviations: AZA, azathioprine; ALL, allopurinol; γ-GT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase
Clinical outcomes are evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.13) The reference value of γ-GT was 13 to 64 IU/L in males and 9 to 32 IU/L in females. The reference value of ALP is 38 to 113 IU/L.
a: Time to outcome was defined as the period from the initiation of combination therapy to the occurrence of outcome at the nadir.
b: Time to recovery was defined as the period from outcome at the nadir to the recovery.
c: Patient 1 discontinued azathioprine and allopurinol on day 28.
d: Patient 2 discontinued azathioprine on day 42.
Clinical courses of adverse events associated with azathioprine are shown in Fig. 1. When adverse events occurred, patient 1 discontinued the combination therapy on day 28, whereas patient 2 discontinued only azathioprine on day 42. Currently, eGFR was comparable with baseline values in the two patients (patient 1; 23.8 mL/min/1.73 m2 on day 28 and patient 2: 41.2 mL/min/1.73 m2 on day 42). Notably, the clinical course of anemia was relatively long irrespective of epoetin beta pegol across shortened intervals or with escalated doses (50 μg to 100 μg). An increase in γ-glutamyl transpeptidase and alkaline phosphatase without total bilirubin elevation was observed in patient 2 (Fig. 1B). Additionally, patient 2 had no instances of alcohol intake. We came across the following clinically negative findings at the beginning of the combination therapy: hepatitis B surface antigen, 0.00 IU/mL; hepatitis B surface antibody, > 1000.0 mIU/mL; hepatitis B core antibody, 8.39 COI; hepatitis C antibody, 0.04 COI. HBV-DNA load in the blood was < 2.1 log10 copies/mL during the study period. Furthermore, patient 2 did not have gastrointestinal symptoms and drug rash due to the other medications such as allopurinol. Thus, patient 2 exhibited a cholestatic pattern of hepatotoxicity associated with azathioprine.
Changes in Clinical Parameters of Patients that Experienced Adverse Events with Azathioprine Use
The X-axis represents days, and day 0 indicates the day patients initiated the combination therapy of azathioprine and allopurinol. Each closed circle represents a data point, and the notable values are written near the corresponding data point. Black and white bars below the x-axis represent the administration of azathioprine and allopurinol. (Fig. 1A) The left Y-axis represents WBC and Net counts, while the right Y-axis represents Hb level. Thin downward arrows indicate a subcutaneous administration of epoetin beta pegol (50 μg). Bold arrows indicate a subcutaneous injection of 100 μg epoetin beta pegol. Patient 1 discontinued the combination of azathioprine and allopurinol on day 28. (Fig. 1B). The left Y-axis represents γ-GT and ALP levels, while the right Y-axis represents the T-Bil level. Patient 2 discontinued azathioprine on day 42. Abbreviations: AZA, azathioprine; ALL, allopurinol; QD, once daily; WBC, white blood cell; Net, neutrophil; Hb, hemoglobin; γ-GT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; T-Bil, total bilirubin.
This study suggests that the drug-drug interaction between azathioprine and allopurinol is clinically relevant, even at low-dose settings in patients with renal impairment. This drug-drug interaction should be taken into consideration to avoid adverse consequences, such as myelosuppression.
Several reports have raised concerns regarding the drug-drug interaction between azathioprine and allopurinol, which are supported by the evidence from most patients that have received a combination of azathioprine (100 to 200 mg daily) and allopurinol (> 100 mg daily).15–17) Our finding demonstrated that low-dose combination therapy of azathioprine and allopurinol increased the risk of adverse events associated with azathioprine (e.g., myelosuppression). However, there was the minimal impact of allopurinol dose reduction on the development of adverse events such as leucopenia, irrespective of a decrease in 6-tioguanine concentration.18) Combination therapy with azathioprine and allopurinol has the potential to develop drug-drug interactions despite a low-dose setting.
Renal function contributes considerably to determining drug-drug interaction between azathioprine and allopurinol. Chronic kidney disease prolongs the half-life of oxypurinol because of the decline of clearance, increasing its blood concentration in late phase.8) Therefore, the increase in oxypurinol concentration in the late phase amplifies the inhibition of XO activity. Additionally, patient 1 was elderly and had sarcopenia (body mass index: 16.1 kg/m2). Due to a decrease in the serum creatinine level, renal function calculated using the eGFR might be overestimated, implying that the serum oxypurinol concentration is elevated beyond expectation. Although myelosuppression might have been induced by azathioprine alone, the inhibition of XO by oxypurinol may have occurred intensively in patient 1 and increased the severity of adverse events associated with azathioprine. Moreover, patient 1 was considered to receive azathioprine with an insufficient dose reduction (1.28 mg/kg) because the prescribing information recommends a 25% to 33% dose reduction during the co-administration of allopurinol (e.g., 0.5 to 0.83 mg/kg).7) As patients with nudix hydrolase 15 (NUDT15) R139C homozygous variant T/T or heterozygous variant C/T often suffered from leukopenia within 8 weeks,19) patient 1 experienced myelosuppression at an early stage. However, we could not conclude that patient 1 carries the T/T or C/T genotype because the allele frequency of NUDT15 R139C is about 20% in Japanese patients.19)
Patient 2 with modest renal impairment developed drug-drug interaction between azathioprine and allopurinol, despite a very low dose of azathioprine (0.44 mg/kg once daily). In fact, allopurinol decreased serum uric acid level from 8.4 mg/dL to 7.1 mg/dL during the study period, indicating that allopurinol certainly blocked XO activity. In a previous study, the frequency of NUDT15 R139C variant C/T accounted for 17% of Japanese patients.19) In the NUDT15 R139C variant C/T group, patients received azathioprine dose with large variability (the maintenance daily dose of 0.57 ± 0.32 mg/kg),19) suggesting that this finding cannot be applied to the drug response in patient 2. Additionally, NUDT15 R139C variant T/T accounted for only 3.7%.19) Thus, since NUDT15 R139C variant T/T is very rare, it is unlikely that patient 2 carried it. In contrast, patient 3, who received azathioprine 0.88 mg/kg once daily and exhibited mild renal impairment, did not experience adverse events by the drug-drug interaction. The fact is that the accumulation of oxypurinol in renal impairment indicated that the drug-drug interaction between azathioprine and allopurinol is likely to occur.20) Notably, patient 3 was younger age. A previous study identified older age as a risk factor for infection during azathioprine treatment.21) Age should be considered in the drug-drug interaction between azathioprine and allopurinol in addition to renal function.
Moreover, adverse events associated with azathioprine persisted for long period. Steady-state of 6-thioguanine nucleotides concentrations were attained after four weeks because the half-life of 6-thioguanine nucleotides was approximately 5 days.22) This knowledge helped to understand the clinical course of the drug-drug interaction. Many randomized controlled trials exclude patients with renal impairment or intolerance to allopurinol, and a combination of azathioprine and allopurinol might be effective and well-tolerated in patients without characteristics such as renal impairment.23,24) We recommend the careful selection of patients who are suitable for combination therapy with azathioprine and allopurinol.
There were many limitations in our study. First, this study is a case-series design, and thus, it was difficult to avoid the impact of unknown confounding factors. Second, we could not analyze genetic polymorphisms of thiopurine methyltransferase and NUDT15, which affect sensitivity to azathioprine. Third, there were no data on the concentration of oxypurinol and 6-thioguanine nucleotides. Fourth, we could not confirm adherence to pharmacotherapy. Finally, we could not obtain periodic clinical laboratory data, therefore, the time courses may be distorted.
In conclusion, adverse events caused by the interaction between azathioprine and allopurinol were characterized by chronic kidney disease in the two patients who received low-dose azathioprine and allopurinol. Renal function may be an important factor for this drug-drug interaction.
We would like to thank Editage for editing and reviewing the manuscript for English language.
Conflict of interestThe authors declare no conflict of interest.
